The present invention relates to novel benzamide inhibitors of the P2X7 receptor, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing them, and their use in therapy. The active compounds of the present invention are useful in the treatment of inflammatory diseases such as osteoarthritis and rheumatoid arthritis; allergies, asthma, COPD, cancer, reperfusion or ischemia in stroke or heart attack, autoimmune diseases and other disorders. The active compounds are also antagonists of the P2X7 receptor.
The P2X7 receptor (previously known as P2Z receptor), which is a ligand-gated ion channel, is present on a variety of cell types, largely those known to be involved in inflammatory/immune process, specifically, macrophages, mast cells and lymphocytes (T and B). Activation of the P2X7 receptor by extracellular nucleotides, in particular adenosine triphosphate, leads to the release of interleukin-1β (IL-1β) and giant cell formation (macrophages/microglial cells), degranulation (mast cells) and proliferation (T cells), apoptosis, and L-selectin shedding (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APC), keratinocytes, salivary acinar cells (parotid cells), hepatocytes and mesangial cells.
P2X7 antagonists are known in the art, such as those described in International Patent Publications WO 01/46200, WO 01/42194, WO 01/44213, WO99/29660, WO 00/61569, WO 99/29661, WO 99/29686, WO 00/71529, and WO 01/44170. Other inhibitors of P2X7 are described in United States Non-provisional application Ser. No. 10/292,887, filed Nov. 12, 2002, which claimed priority to U.S. Provisional Application 60/336,781, filed Nov. 12, 2001. Other adamantyl P2X7 inhibitors are described in U.S. Non-provisional application Ser. No. 10/292,886 filed Nov. 12, 2002 which claimed priority to U.S. provisional application 60/336,892 filed Nov. 12, 2001. Yet other P2X7 inhibitors are described in U.S. Provisional Application 60/437,228 and 60/437,505 both filed Dec. 31, 2002. Each of the foregoing application is incorporated herein by reference in their entirety.
Benzamides, heteroarylamides and reverse amides for uses other than inhibition of the P2X7 receptor are described in various publications, such as International Patent Publications WO 97/22600, EP 138,527, WO 00/71509, WO 98/28269, WO 99/17777 and WO 01/58883.